Tetanus is an acute infectious disease caused by the anaerobic bacteria Clostridium tetani. A potent protein neurotoxin elaborated by the bacteria causes the manifestations of the disease. Typically, tetanus is characterized by neurological symptoms including convulsions and intermittent muscle spasms. Lockjaw is a common name for the disease. The neurotoxin inhibits neurotransmitter release by an undetermined mechanism of action believed to require at least three steps: 1) binding to a eukaryotic cell receptor, 2) translocation to the cytosol and 3) disruption of the secretory pathway.
The precise structure of the receptor for tetanus toxin has not been identified. Tetanus toxin binds to certain gangliosides present on neuronal cells, and some studies indicate that these gangliosides may act as the cellular receptor for tetanus toxin. It has also been proposed that tetanus toxin must interact with gangliosides plus an additional receptor in order for intoxication to proceed.
A vaccine based on the tetanus toxin, referred to as tetanus toxoid, causes the individual to produce antitoxin antibodies and thus provides active immunity. Survival of the patient after an active injection of tetanus does not cause immunity to further episodes of tetanus because the amount of neurotoxin sufficient to cause the disease is less than the amount of neurotoxin necessary to produce active immunity.
Anti-tetanus toxin immunoglobulins derived from humans are available to produce passive immunity. Equine tetanus antitoxin is also available, but it is less favored because of a shorter half-life and greater problems with hypersensitivity and serum sickness as compared to the human immunoglobulin.
Active immunization against tetanus, as well a number of other diseases, is routinely recommended for all members of the population. Typical immunization schedules begin with infants. The usual recommendation is four doses of tetanus toxoid vaccine by about 18 months of age with a fifth dose before entering school at about age 4 or 5. Normally, the vaccination is repeated about every 5 to 10 years thereafter depending on the individual's exposure to tetanus.
The current tetanus vaccine licensed for human and veterinary use consists of tetanus toxin which has been chemically inactivated and partially purified. Typically, the toxin is treated with formaldehyde, but alternatively it may be treated with glutaraldehyde to become atoxic. This product produces long lasting immunity, but is poorly characterized and contains impurities which can cause adverse side effects. Although the toxin itself is innocuous when it has been treated in a form suitable for use in a vaccine, contaminants or other components of the vaccine may cause adverse reactions. Because the neurotoxin is purified from lysed Clostridium tetani cells, the process is time-consuming and involves some risk due to the production of the bacterial cultures which include a potent toxin.
Contaminants either from the lysed cells or from the procedure used to make the toxin atoxic can cause vaccination reactions in the individual patient. Furthermore, the conventional tetanus vaccines must be kept under refrigeration. This causes difficulties in transportation and storage which may be significant problems in underdeveloped regions where the vaccine may be most desperately needed. Recently, in the U.S., the overall death rate for tetanus was about 30%. Improved immunization status of the population can help decrease this mortality.
Tetanus toxin has 1315 amino acids and is synthesized by C. tetani as a single polypeptide chain that is proteolyzed to yield two fragments, the light chain (LC) derived from the amino terminus, and the heavy chain (HC) derived from the carboxyl terminus. The heavy chain has a molecular weight of about 100,000 and the light chain of about 50,000. The two chains are linked by a single disulfide bond and noncovalent interactions.
The heavy chain can be readily proteolyzed by papain and other proteases at one additional site resulting in formation of two fragments: the light chain linked by a disulfide bond to approximately one-half of the heavy chain (L-HC.sub.n) including the amino terminal, and the carboxyl terminal one-half of the heavy chain (H.sub.c) or Fragment C. Each of the three fragments of tetanus toxin appears to represent a functional domain necessary for different steps in intoxication. The LC is responsible for intoxication of target cells, and the H.sub.cn fragment has been proposed to translocate tetanus toxin across membranes. The H.sub.c fragment, or Fragment C, is required for recognition of and binding to target cells. This fragment also retains the ability of intact tetanus toxin to undergo retrograde axonal transport.